Traditional Approach:

• 10-year ASCVD risk (PCE)
• Treatment at thresholds (≥7.5%)
• Static, single time point

The Question:

“Who will have an event in the next 10 years?”

What’s Missing:

• Young patients with high lifetime risk
• Different disease trajectories
• Optimal intervention timing
• Information that accrues over time

Better Question:

“What is their lifetime burden, and when should we intervene?”

Profile:

• High polygenic risk score (PRS) or FH
• Elevated LDL from young age
• CAD by age 45-50

Key Evidence:

• Ference, NEJM 2012: Lifetime cholesterol lowering >> short-term intensive
• Khera, Nat Genet 2018: PRS identifies missed high-risk individuals
• AHA 2022: PRS highly predictive in younger populations

The Concept:

Genetics provides early signal → Lower threshold for intervention

Progression:

1. Prediabetes (age 40-45)
2. Type 2 diabetes (age 45-50)
3. Metabolic syndrome (age 50-55)
4. CAD (age 55-60)

Key Evidence:

• DPP: Lifestyle intervention delays diabetes
• Look AHEAD: Weight loss reduces CV events
• EMPA-REG, LEADER: GLP-1/SGLT2i benefit

The Concept:

Biomarkers accumulate → Intervene at transition points

Profile:

• Rheumatologic disease (RA, psoriasis)
• Often normal lipids
• “Low” 10-year PCE risk
• Chronic systemic inflammation

Key Evidence:

• CANTOS: IL-1β inhibition reduces CV events
• Colchicine trials: Anti-inflammatory benefit
• ACC Statement: Inflammation as CV target

The Concept:

Alternative risk pathway → Missed by traditional models

Characteristics:

• Maintained low risk across decades
• Favorable genetics + lifestyle?
• Resilience to aging

Questions:

• What protects this group?
• Can we replicate their trajectory?
• Genomics? Lifestyle? Microbiome?

The Concept:

Learn from success → Identify protective factors

Starting Point (Age 30-40):

• Genetics (fixed)
  • Polygenic risk scores
  • Family history
  • Monogenic conditions (FH)

This provides the baseline trajectory

Over Time (Age 40-70):

• Biomarkers (dynamic)
  • Serial lipids, BP, glucose
  • Inflammatory markers
  • Novel biomarkers
• Imaging (periodic)
  • CAC scoring
  • Carotid ultrasound
  • CT angiography
• Events (sentinel)
  • Diabetes diagnosis
  • Hypertension
  • Other comorbidities

Uncertainty decreases as information accumulates

Available Now:

• LIVE-CVD: Lifelong benefit calculator
• PRS: Clinical labs offer testing ($50-200)
• CAC scoring: Widely available imaging
• SCOT-HEART: CT angiography trials

On the Horizon:

• AI-enhanced imaging
• EHR-embedded calculators
• Continuous monitoring (wearables)
• Multi-omics integration

Challenges:

• Clinical:
  • EHR integration
  • Workflow burden
  • Training needed
• Payer:
  • Coverage for “healthy” patients
  • Long-term value demonstration
  • Reimbursement models
• Patient:
  • Understanding lifetime risk
  • Motivation for prevention
  • Health literacy

The Core Concept:

• Multiple trajectories to CVD
• Genetics provides early signal
• Information accumulates over time
• Uncertainty decreases with data

The Opportunity:

• Earlier intervention for high-risk trajectories
• Avoid overtreatment of low-risk
• Precision prevention timing

The Path Forward:

• Integrate genetics + biomarkers + imaging
• Build clinical decision support
• Demonstrate cost-effectiveness
• Engage stakeholders (payers, clinicians, patients)

The Question:

How do we move from 10-year risk thresholds to lifetime trajectory management?